During events ranging from host defense to chronic inflammatory disease states, monocytes/macrophages (MOs) infiltrate affected interstitial tissues where they can participate in both the proteolytic remodeling of the extracellular matrix and local immune responses. While Ms have long been assumed to mobilize proteolytic enzymes (particularly those belonging to the matrix metalloproteinase gene family) in order to traffic through extracellular matrix barriers, increasing evidence suggests that myeloid cell populations infiltrate tissues via protease-independent processes relying instead on the mechanical distortion of cell shape. Hence, while MOs express matrix metalloproteinases, the function of these enzymes remain unclear. In an attempt to identify alternate matrix metalloproteinase-dependent functions in MOs, we have focused our attention on the membrane-anchored protease, MT1-MMP. In preliminary studies designed to compare and contrast the tissue-invasive behavior of wild-type and MT1-MMP-null MOs, we find that MO-derived MT1-MMP does not, as predicted, play a required role in regulating cell trafficking in vitro or in vivo. Instead, gene expression profiling of MT1-MMP+/+ versus MT1-MMP-/- MOs suggest that the protease acts as a critical but unsuspected, transactivator of the gene networks central to MO inflammatory responses. Evidence suggests that MT1-MMP may exert this effect by controlling a heretofore undescribed axis wherein LPS-TLR4 interactions trigger MT1-MMP expression which then acts as a required activator of PI3K?/Akt/GSK3 signaling and the Mi-2/NuRD complex of nucleosome remodeling factors. In combination with an additional body of preliminary data supporting the possibility that MT1-MMP traffics into the nuclear compartment, we postulate that MT1-MMP serves as co-transcriptional activators critical to immune regulation. As such, we propose to i) characterize the functional status of the LPS-TLR4 axis in MT1-MMP-/- macrophages in vitro, ii) define the MT-MMP-initiated cascades that link PI3K?-Akt-GSK3 signaling to Mi-2/NuRD-dependent nucleosome remodeling, iii) characterize the MT-MMP nuclear trafficking pathway that control MO immune responses. These studies should provide new and novel insights into the orchestration of MO-dependent extracellular matrix turnover with the nucleosomal remodeling pathways that mark chronic inflammatory events central to host defense as well as inflammatory disease states. As MT-MMPs and PI3K? are expressed in almost all immune cell populations, these results should serve to outline a new paradigm in inflammation and identification of control mechanisms that may prove conducive to therapeutic intervention.